The rhesus monkey is a model of normal human aging that enables cognitive testing to be followed by optimal preservation of brain tissue for multidisciplinary studies. The proposed studies will test the hypothesis that age-related cognitive decline results from a cascade of mild degenerative changes beginning in early middle age with inflammation and damage in white matter that leads to functional changes in axons and progresses to functional and structural changes in neurons. We will study three cohorts of monkeys to test various aspects of this hypothesis. The first cohort of 36 monkeys will be used in a cross-sectional study and consist of subjects covering the adult life span from 5 to 30 years old. After behavioral testing, MRI scans will be followed by in vivo neurophysiology and a new two stage perfusion fixation to provide fresh and fixed tissue to identify brain changes underlying cognitive decline. A second cohort of 6 middle aged monkeys will be treated like cohort 1 except they will be perfusion fixed with mixed aldehydes for electron microscopy to supplement existing samples and allow identification of the ultrastructural changes that are the first changes to appear in middle age in association with cognitive decline. A third cohort of 12 early middle aged monkeys (ages 13-15) will be followed longitudinally for 4+ years with repeated behavioral testing, MRI scans of the brain, and samples of blood and CSF. As the prevalence of cognitive impairment is low at 13-15 but high by 20, behavioral data will identify the cognitive profile and rate of decline of individual monkeys. Longitudinal MRIs will reveal concurrent changes in the in vivo brain structure, and CSF and blood samples will allow biomarkers to be followed. For cohorts 1 and 3, perfusion fixation will be preceded by in vivo neurophysiological assessment of compound action potentials. Then the two stage perfusion will follow to allow immediate collection of unfixed samples from one hemisphere before the remainder of the brain is fixed. Fresh tissue will be used for in vitro neurophysiology of synaptic currents and action potentials, for single cell PCR, and for biochemical and molecular studies of underlying mechanisms. Fixed tissue will be used for anatomical studies, including stereological studies of neuron numbers and immunocytochemical studies of inflammation and other degenerative processes. REVIEW OF INDIVIDUAL COMPONENETS CORE A: ADMINISTRATIVE AND DATA MANAGEMENT CORE;Dr. Douglas Rosene (CL) DESCRIPTION (provided by applicant): The Administrative Core is responsible for the overall scientific direction and financial and administrative management of this Program Project. To accomplish this the core will handle all orders and maintain appropriate financial records for all of the Cores and Projects. It will also provide administrative and clerical support to the Cores and Projects in preparation of manuscripts and the annual progress reports. The core will also organize biweekly meetings of the Program Project staff (all project and core leaders and their coinvestigators) at which scientific direction and progress will be discussed and decisions about priorities or new directions made and will also organize meetings of the External Advisory Committee (outside scientists selected to provide expertise in the areas we are investigating) in years two and four of the Program. These will be one day, off campus meetings at which the Program Project staff will present summaries of the their work to the advisors in the morning and then the afternoon will be devoted to round table discussion with the advisors. This group meeting will allow us to get their input on the overall scientific direction of this Program. Finally, the core will also provide statistical support for all of the Cores and Projects and will maintain the Archival Program Database of Program Project Data.